Generally, a preservative is indispensable in (multidose) aqueous liquid compositions. A representative of such a preservative is Benzalkonium chloride. However, frequent application of an ophthalmic solution containing benzalkonium chloride or application thereof to those who have corneal injury or abnormal tear dynamics such as dry eye syndrome causes side effects and corneal damage (Non Patent Literature 1 and 2). Therefore, it is desirable that the concentration of benzalkonium chloride added to ophthalmic solutions etc. is low. Considering both preservative efficacy and safety, a desirable concentration of benzalkonium chloride added to an ophthalmic solution is said to be 0.002% to 0.005% (Non Patent Literature 1). Aqueous liquid bromfenac compositions containing 0.001% or 0.005% benzalkonium chloride are known (Patent Literature 1 to 7). However, the preservative efficacy of the compositions is unknown.
Bromfenac (2-amino-3-(4-bromobenzoyl)phenylacetic acid) is a non-steroidal anti-inflammatory drug of which the preservative efficacy is unknown.
Benzalkonium chloride is a cationic surfactant which is widely used as a preservative for topical aqueous liquids as mentioned above. A preferred concentration of benzalkonium chloride, in particular in ophthalmic solutions, is 0.002% to 0.005%, but the preservative efficacy of benzalkonium chloride can decline under the influence of other substances in an aqueous base. For example, a large amount of a non-ionic surfactant added to an aqueous liquid impairs the preservative efficacy of benzalkonium chloride (Patent Literature 8). It is also known that benzalkonium chloride forms complexes with other substances in an aqueous liquid, resulting in impaired preservative efficacy. In particular, it is reported that a combination of a non-steroidal anti-inflammatory drug (NSAID) and a quaternary ammonium salt such as benzalkonium chloride forms a complex, resulting in decline in the preservative efficacy (Patent Literature 9 and 10).
No aqueous liquid bromfenac composition which has sufficient preservative efficacy and stability as a result of combining bromfenac and a base which contains benzalkonium chloride but does not have sufficient preservative efficacy has so far been reported.